Marc H. V. van Regenmortel, a virtual friend and a real colleague

Abstract

Unlike Jean-Luc Pellequer and Eric Westhof,¹ who were colleagues of Marc H.V. van Regenmortel, I have never met him in person. However, I can add my voice to the discussion of how contingency or serendipity has led me to productively collaborate with Marc (unfortunately, exclusively in the on-line format), resulting in the publication of a joint paper in 2020.² Before moving to this part of my story, a short historical excurse is needed.

My first (once again, exclusively virtual) encounter with Marc took place in 2004, when he played a crucial role in our work on one of the first comprehensive reviews on the roles of intrinsically disordered proteins and regions (IDPs/IDRs) in molecular recognition, regulation, and cell signaling.³ In the middle of 2004, I joined the Center for Computational Biology and Bioinformatics (CCBB) at the Indiana University-Purdue University at Indianapolis (IUPUI) that was created and headed by Prof. A. Keith Dunker, whom I worked with for 6 years on different aspects of the protein intrinsic disorder phenomenon. One of my first projects there was analysis of the then-available literature data on the functionality of intrinsic disorder.

By that time, it became clear that although IDPs/IDRs have been mostly ignored by the scientific community since the inception of the lock-and-key model by Hermann Emil Louis Fischer (1852–1919) in 1894,^{4, 5} many aspects of protein functionality could not be explained using this important model and its associated sequence-structure-function paradigm. In fact, many protein functions do not require specific structures, instead relying on conformational flexibility, and as a result, many biologically active proteins (or protein regions) do not have unique structures, instead being intrinsically disordered.^6-15 However, the concept of functional disorder was still met with strong skepticism by the scientific community, especially by those who worked in structural biology.

This brings us to my first example of Marc-centric contingency or serendipity. When Keith contacted Marc to check if the manuscript we were working on would fit the scope of the Journal of Molecular Recognition, to our big surprise, we received very enthusiastic support. Those times were still the early days of protein intrinsic disorder, and many scientific journals were simply dismissing the idea of functional disorder as nonsensical (as an example, it took more than a year to publish my first paper on this subject (Ref. 16), which was rejected by 14 journals before being eventually accepted by Proteins⁷). During the preparation of the manuscript for the Journal of Molecular Recognition, we had a productive exchange with Marc, which was very useful and is reflected in the acknowledgement in the resulting paper that reads “Both A.K.D. and V.N.U. thank M.H.V. van Regenmortel for shepherding this review from its inception to its final form with diligence and insight.”³ According to the Web of Science, as of February 18, 2024, this review paper has been cited over 665 times and now occupies position # 3 in the list of the most cited papers published in the Journal of Molecular Recognition (https://www-webofscience-com.ezproxy.lib.usf.edu/wos/woscc/summary/9142e292-c3cd-47c1-8099-c250aa2a492e-cce4fea4/times-cited-descending/1). This part of the story, in my view, illustrates the bravery, open mindedness, foresight, and wisdom of Marc.

A total of 15 years later (at the end of 2019), I received a very kind personal invitation from Marc to prepare a review paper for the Journal of Molecular Recognition on the subject of molecular recognition, intrinsically disordered proteins, and biological complexity. In that letter, he wrote: “In your 2018 paper,¹⁷ you referred to the fact that ‘early’ amino acid residues tended to be disorder-promoting while ‘late’ residues were more order-generating. I have always been puzzled by the fact that complementary codon triplets always code for residues of opposite polarity (hydrophilic vs. hydrophobic) leading to short peptides that bind to each other by hydropathic complementarity.¹⁸ Could there be some link between the ‘age’ of residues and this phenomenon of early gene products being selected for binding to each other in the early RNA world?”

My curiosity was immediately ignited by this question and I enthusiastically accepted his invitation: “Thank you very much for your letter and a kind invitation to write a review for your Journal of Molecular Recognition on Molecular recognition, intrinsically disordered proteins, and biological complexity. The idea is very appealing, and I am delighted to accept your invitation… As far as your idea that there could be a link between the ‘age’ of residues, the hydropathic complementarity phenomenon you mentioned, and selection of early gene products for binding to each other in the early RNA world, I think that this is a very interesting hypothesis that should definitely be checked. However, I have to think about this.” To that he replied: “I am very grateful that you have accepted my invitation to write the review for JMR… I am also pleased that you think that the hydropathic binding of peptides derived from codons and anticodons is a phenomenon that merits attention because there seems to be no exception to the rule that short peptides obtained in this manner bind to each other. It might thus have contributed to the development of the genetic code as we know it today if the hydropathic complementarity of these early gene products played a role in the initial functional selection of peptide sequences that recognize each other (linking RNA and peptide sequence). I often quote Lily Kay's phrase¹⁹: “The Book of Life produces information without meaning, codes with no language, messages with no sender and writing devoid of authorship.” “Human languages needed consciousness to come about, and we no longer believe that a ‘designer’ is responsible for developing the genetic code. Some evolutionary mechanism must be responsible for it, and a stochastic mechanism seems to beg the question. A link between short complementary RNAs and short complementary functional peptides could perhaps lead to a better explanation”.

Even if I had had any second thoughts (which I did not), this message would convince me that I need to jump into this study. A few months later, the work was completed, and I sent the rough draft to Marc with a cover note stating: “Since this work on intrinsic disorder and sense-antisense recognition in proteins was completely inspired by our conversation and represents my attempt to answer your question on disorder, complementarity, and evolution, I think that you should be a coauthor. I really hope that you will accept this role. Once again, this work would not be possible if it would not be for you and your questions.” Needless to say that I was very happy to get his positive reply a few days later and was even happier when this joint paper was published later that year in the Journal of Molecular Recognition.²

These two short stories represent just two brush strokes on the portrait of Marc van Regenmortel, my virtual friend and a real colleague.

The author has no relevant financial or non-financial interests to disclose.